Branchio-oto-renal syndrome (BOR): novel mutations in the EYA1 gene, and a review of the mutational genetics of BOR

Department of Genetics, Boys Town National Research Hospital, Omaha, Nebraska 68164, USA.
Human Mutation (Impact Factor: 5.05). 04/2008; 29(4):537-44. DOI: 10.1002/humu.20691
Source: PubMed

ABSTRACT Branchio-oto-renal syndrome (BOR) is an autosomal dominant disorder characterized by the association of branchial and external ear malformations, hearing loss, and renal anomalies. The phenotype varies from ear pits to profound hearing loss, branchial fistulae, and kidney agenesis. The most common gene mutated in BOR families is EYA1, a transcriptional activator. Over 80 different disease-causing mutations have been published (, last accessed 20 November 2007). We analyzed the EYA1 coding region (16 exons) from 435 families (345 at the University of Iowa [UI] and 95 at Boys Town National Research Hospital [BTNRH], including five at both) and found 70 different EYA1 mutations in 89 families. Most of the mutations (56/70) were private. EYA1 mutations were found in 31% of families (76/248) fitting established clinical criteria for BOR and 7% of families with questionable BOR phenotype (13/187). Severity of the phenotype did not correlate with type of mutation nor with the domain involved. These results add considerably to the spectrum of EYA1 mutations associated with BOR and indicate that the BOR phenotype is an indication for molecular studies to diagnose EYA1-associated BOR.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Haploinsufficiency of Eya1 causes the branchio-oto-renal (BOR) syndrome and abnormally high levels of Eya1 are linked to breast cancer progression and poor prognosis. Therefore, regulation of Eya1 activity is key to its tissue-specific functions and oncogenic activities. Here, we show that Eya1 is post-translational modified by ubiquitin and its ubiquitination level is self-limited to prevent premature degradation. Eya1 has an evolutionarily conserved CDC4 phospho-degron (CPD) signal, a target site of GSK3 kinase and Fbw7 ubiquitin ligase, which is required for Eya1 ubiquitination. Genetic deletion of Fbw7 and pharmacological inhibition of GSK3 significantly decreases Eya1 ubiquitination. Conversely, activation of the PI3K/Akt and the canonical Wnt signal suppresses Eya1 ubiquitination. Compound Eya1(+/-);Wnt9b(+/-) mutants exhibit an increased penetrance of renal defect, indicating that they function in the same genetic pathway in vivo. Together, these findings reveal that the canonical Wnt and PI3K/Akt signal pathway restrain the GSK3/Fbw7-dependent Eya1 ubiquitination, and further suggest that dysregulation of this novel axis contributes to tumorigenesis.
    Molecular and Cellular Biology 04/2014; 34(13). DOI:10.1128/MCB.00104-14 · 5.04 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Human endogenous retroviral (HERV) sequences are the remnants of ancient retroviral infection and comprise approximately 8% of the human genome. The high abundance and interspersed nature of homologous HERV sequences make them ideal substrates for genomic rearrangements. A role for HERV sequences in mediating human disease-associated rearrangement has been reported but is likely currently underappreciated.Methods and ResultsIn the present study, two independent de novo 8q13.2-13.3 microdeletion events were identified in patients with clinical features of Branchio-Oto-Renal (BOR) syndrome. Nucleotide-level mapping demonstrated the identical breakpoints, suggesting a recurrent microdeletion including multiple genes such as EYA1, SULF1, and SLCO5A1, which is mediated by HERV1 homologous sequences.Conclusions These findings raise the potential that HERV sequences may more commonly underlie recombination of dosage sensitive regions associated with recurrent syndromes.
    BMC Medical Genetics 08/2014; 15(1):90. DOI:10.1186/PREACCEPT-1532986649107199 · 2.45 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cleft lip and/or cleft palate (CL/P) collectively are well known as being amongst the most common birth defects but we still have difficulty explaining why the majority of cases occur. In general, sporadic cases with no family history may be more related to environmental risks, while the presence of one or more affected relative in the same family strongly suggests that genetic factors are the main contributor. Orofacial clefts can occur in conjunction with other defects (syndromic CL/P) or as an isolated defect (non-syndromic - NSCL/P). CL/P syndromes have been studied intensively and appear to have a stronger genetic aetiology. Here we report on the relationship between syndromic and NSCL/P as a phenotypic spectrum resulting from coding or non-coding mutations respectively. We review certain abnormalities that are most frequently associated with CL/P, including dental, heart, brain, skin and certain types of cancer and examine some of the genes that are involved. We include the outcome of recent NSCL/P GWAS data and we will discuss how the genes at these loci might contribute towards clarifying the genetics of CL/P.
    European journal of medical genetics 04/2014; DOI:10.1016/j.ejmg.2014.04.003 · 1.49 Impact Factor

Full-text (2 Sources)

Available from
May 26, 2014